US2018169095A1PendingUtilityA1

The use of sgc stimulators, sgc activators, alone and combinations with pde5 inhibitors for the treatment of digital ulcers (du) concomitant to systemic sclerosis (ssc)

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Assignee: Bayer Pharma AGPriority: May 6, 2015Filed: May 2, 2016Published: Jun 21, 2018
Est. expiryMay 6, 2035(~8.8 yrs left)· nominal 20-yr term from priority
Inventors:Claudia Hirth-DietrichPeter SandnerJohannes-Peter StaschMichael HahnMarkus FollmannAlexandros Vakalopoulos
A61K 31/5377A61P 17/02A61K 2300/00A61K 45/06A61K 31/519A61K 31/426A61K 31/506A61K 31/4439A61K 31/635A61K 31/53A61K 31/437A61K 31/427A61K 31/197
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Claims

Abstract

Use of sGC stimulators, sGC activators alone, or in combination with PDE5 inhibitors for the prevention and healing of Digital Ulcers which are concomitant to fibrotic diseases, such as systemic sclerosis and scleroderma.

Claims

exact text as granted — not AI-modified
1 - 12 . (canceled) 
     
     
         13 . A method for the prevention and healing of digital ulcers that are concomitant to fibrotic diseases comprising administering a therapeutically effective amount of a sGC stimulator or activator alone or in combination with a PDE5 inhibitor to a patient in need thereof. 
     
     
         14 . A method for the prevention and healing of digital ulcers that are concomitant to fibrotic diseases, comprising administering a therapeutically effective amount of a sGC stimulator or activator selected from the group consisting of 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-5-(4-morpholinyl)-4,6-pyrimidinediamine (1), 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-5-(4-pyridinyl)-4-pyrimidine amine (2), methyl-4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-5-pyrimidinyl(methyl)carbamate (3), methyl-4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-5-pyrimidinylcarbamate (4), 4-({(4-carboxybutyl)[2-(2-{[4-(2-phenylethyl)benzyl]oxy}phenyl)ethyl]amino}methyl) carboxylic acid (5), methyl-{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]pyrimidine-5-yl}carbamate (6), methyl-{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]pyrimidine-5-yl}methylcarbamate (7), methyl-{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]pyrimidine-5-yl}(2,2,2-trifluoroethyl)carbamate (8), 5-chloro-2-(5-chlorothiophene-2-sulfonylamino-N-(4-(morpholine-4-sulfonyl)-phenyl)-benzamid as sodium salt (9), 2-(4-chloro-phenylsulfonylamino)-4,5-dimethoxy-N-(4-(thiomorpholine-4-sulfonyl)-phenyl)-benzamide (10), 1-{6-[5-chloro-2-({4-trans-4-}trifluoromethyl)cyclohexyl]benzyl}oxy)phenyl]pyridine-2-yl}-5-(trifluoromethyl)-1H-pyrazol-4-carboxylic acid (11), 1-[6-(2-(2-methyl-4-(4-trifluoromethoxyphenyl)benzyloxy)-phenyl)pyridine-2-yl]-5-trifluoromethyl-pyrazol-4-carboxylic acid (12), 1[6-(3,4-dichlorophenyl)-2-pyridinyl-5-(trifluoromethyl)-1H-pyrazole-4-caboxylic acid (13), 1-({2-[3-chlor-5-(trifluoromethyl)phenyl]-5-methyl-1,3-thiazole-4-yl}methyl)-1H-pyrazole-4-carboxylic acid (14), 4-({2-[3-(trifluoromethyl)phenyl]-1,3-thiazole-4-yl}methyl)benzoic acid (15), 1-({2-[2-fluoro-3-(trifluoromethyl)phenyl]-5-methyl-1,3-thiazole-4-yl}methyl)-1H-pyrazole-4-carboxylic acid (16), 4-amino-2-[5-chloro-3(3,3,3-trifluoropropyl)-1H-indazol-1 yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidine-6-one (17), 4-amino-2-[5-chloro-3-(2,3,6-trifluorobenzyl)-1H-indazol-1 yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidine-6-one (18), 4-amino-5,5-dimethyl-2-[3-(2,3,6-trifluorobenzyl)1H-thieno[3,4-c]pyrazol-1-yl]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidine-6-one (19), 4-amino-5,5-dimethyl-2-[3-(2,3,6-trifluorobenzyl)-1H-thieno[2,3-d]pyrazole-1-yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidine-6-one (20), 4-amino-5,5-dimethyl-2-[7-(2,3,6-trifluorobenzyl)imidazo[1,5-b]pyridazine-5-yl]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidine-6-one (21), 4-amino-2-[6-chloro-3-(2,3,6-trifluorobenzyl)imidazo[1,5-a]pyridine-1-yl]]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidine-6-one (22), 4-amino-2-[6-fluoro-3-(2,3,6-trifluorobenzyl) imidazo[1,5-a]pyridine-1-yl]]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidine-6-one (23), 4-amino-2-[6-fluoro-3-(2,3,6-trifluorobenzyl)6-fluoroimidazo[1,5-a]pyridine-1-yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidine-6-one (24), 4-amino-5,5-dimethyl-2-[3-(2,4,6-trifluorobenzyl)imidazo[1,5-a]pyridine-1-yl]]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidine-6-one (25), 4-amino-2-[3-(2-cyclopentylethyl)imidazo[1,5-a]pyridine-1-yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidine-6-one (26), 3-(4-amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine (27), and 2-{5-fluoro-1-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}-5-methyl-5-(trifluoromethyl)-4-[(3,3,3-trifluoropropyl)amino]-5,7-dihydro-6H-pyrrol[2,3-d]pyrimidin-6-one (28) to a patient in need thereof. 
     
     
         15 . The method of  claim 14 , wherein the digital ulcers are concomitant to fibrotic diseases that are systemic sclerosis or scleroderma. 
     
     
         16 . The method of  claim 14 , wherein sGC stimulator or activator is selected from the group consisting of 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-5-(4-morpholinyl)-4,6-pyrimidinediamine (1), 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-5-(4-pyridinyl)-4-pyrimidine amine (2), methyl-4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-5-pyrimidinyl(methyl)carbamate (3), methyl-4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-5-pyrimidinylcarbamate (4), methyl-{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]pyrimidine-5-yl}carbamate (6), methyl-{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]pyrimidine-5-yl}methylcarbamate (7), 3-(4-amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine (27), and 2-{5-fluoro-1-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}-5-methyl-5-(trifluoromethyl)-4-[(3,3,3-trifluoropropyl)amino]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (28). 
     
     
         17 . The method of  claim 16 , wherein the digital ulcers are concomitant to fibrotic diseases that are systemic sclerosis or scleroderma. 
     
     
         18 . The method of  claim 16 , wherein the sGC stimulator or activator is selected from the group consisting of methyl-4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-5-pyrimidinyl(methyl)carbamate (3), methyl-{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]pyrimidine-5-yl}carbamate (6), methyl-{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]pyrimidine-5-yl}methylcarbamate (7), and 2-{5-fluoro-1-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}-5-methyl-5-(trifluoromethyl)-4-[(3,3,3-trifluoropropyl)amino]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (28). 
     
     
         19 . The method of  claim 18 , wherein the digital ulcers are concomitant to fibrotic diseases that are systemic sclerosis or scleroderma. 
     
     
         20 . The method of  claim 16 , wherein the sGC stimulator or activator is methyl-4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-5-pyrimidinyl-(methyl)carbamate (3). 
     
     
         21 . The method of  claim 20 , wherein the digital ulcers are concomitant to fibrotic diseases that are systemic sclerosis or scleroderma. 
     
     
         22 . The method of  claim 13 , wherein a therapeutically effective amount of a sGC stimulator or activator in combination with a PDE5 inhibitor is administered. 
     
     
         23 . The method of  claim 22 , wherein the sGC stimulator or activator is selected from the group consisting of 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-5-(4-morpholinyl)-4,6-pyrimidinediamine (1), 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-5-(4-pyridinyl)-4-pyrimidine amine (2), methyl-4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-5-pyrimidinyl(methyl)carbamate (3), methyl-4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-5-pyrimidinylcarbamate (4), methyl-{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]pyrimidine-5-yl}carbamate (6), methyl-{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]pyrimidine-5-yl}methylcarbamate (7), 3-(4-amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine (27), and 2-{5-fluoro-1-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}-5-methyl-5-(trifluoromethyl)-4-[(3,3,3-trifluoropropyl)amino]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (28) and the PDE5 inhibitor is selected form the group consisting of vardenafil, sildenafil, tadalafil, udenafil, dasantafil, avanafil, mirodenafil, lodenafil, UK 369.003, UK 371.800, SLx2101 and LAS34179. 
     
     
         24 . The method of  claim 23 , wherein the digital ulcers are concomitant to fibrotic diseases that are systemic sclerosis or scleroderma. 
     
     
         25 . The method of  claim 23 , wherein the sGC stimulator or activator is methyl-{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]pyrimidine-5-yl}carbamate (6), methyl-{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]pyrimidine-5-yl}methylcarbamate (7) or 2-{5-fluoro-1-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}-5-methyl-5-(trifluoromethyl)-4-[(3,3,3-trifluoropropyl)amino]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (28). 
     
     
         26 . The method of  claim 23 , wherein the PDE5 inhibitor is vardenafil or sildenafil. 
     
     
         27 . The method of  claim 25 , wherein the PDE5 inhibitor is vardenafil or sildenafil. 
     
     
         28 . A method for accelerating wound healing of digital ulcers that are concomitant to fibrotic diseases, the method comprising administering a therapeutically effective amount of a sGC stimulator or activator alone or in combination with a PDE5 inhibitor to a patient in need thereof. 
     
     
         29 . A method for accelerating wound healing of digital ulcers that are concomitant to fibrotic diseases, the method comprising administering a therapeutically effective amount of a sGC stimulator or activator selected from the group consisting of 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-5-(4-morpholinyl)-4,6-pyrimidinediamine (1), 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-5-(4-pyridinyl)-4-pyrimidine amine (2), methyl-4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-5-pyrimidinyl(methyl)carbamate (3), methyl-4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-5-pyrimidinylcarbamate (4), 4-({(4-carboxybutyl)[2-(2-{[4-(2-phenylethyl)benzyl]oxy}phenyl)ethyl]amino}methyl) carboxylic acid (5), methyl-{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]pyrimidine-5-yl}carbamate (6), methyl-{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]pyrimidine-5-yl}methylcarbamate (7), methyl-{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]pyrimidine-5-yl}(2,2,2-trifluoroethyl)carbamate (8), 5-chloro-2-(5-chlorothiophene-2-sulfonylamino-N-(4-(morpholine-4-sulfonyl)-phenyl)-benzamid as sodium salt (9), 2-(4-chloro-phenylsulfonylamino)-4,5-dimethoxy-N-(4-(thiomorpholine-4-sulfonyl)-phenyl)-benzamide (10), 1-{6-[5-chloro-2-({4-trans-4-}trifluoromethyl)cyclohexyl]benzyl}oxy)phenyl]pyridine-2-yl}-5-(trifluoromethyl)-1H-pyrazol-4-carboxylic acid (11), 1-[6-(2-(2-methyl-4-(4-trifluoromethoxyphenyl)benzyloxy)-phenyl)pyridine-2-yl]-5-trifluoromethyl-pyrazol-4-carboxylic acid (12), 1[6-(3,4-dichlorophenyl)-2-pyridinyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (13), 1-({2-[3-chlor-5-(trifluoromethyl)phenyl]-5-methyl-1,3-thiazole-4-yl}methyl)-1H-pyrazole-4-carboxylic acid (14), 4-({2-[3-(trifluoromethyl)phenyl]-1,3-thiazole-4-yl}methyl)benzoic acid (15), 1-({2-[2-fluoro-3-(trifluoromethyl)phenyl]-5-methyl-1,3-thiazole-4-yl}methyl)-1H-pyrazole-4-carboxylic acid (16), 4-amino-2-[5-chloro-3(3,3,3-trifluoropropyl)-1H-indazol-1 yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidine-6-one (17), 4-amino-2-[5-chloro-3-(2,3,6-trifluorobenzyl)-1H-indazol-1yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidine-6-one (18), 4-amino-5,5-dimethyl-2-[3-(2,3,6-trifluorobenzyl) 1H-thieno[3,4-c]pyrazol-1-yl]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidine-6-one (19), 4-amino-5,5-dimethyl-2-[3-(2,3,6-trifluorobenzyl)-1H-thieno[2,3-d]pyrazole-1-yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidine-6-one (20), 4-amino-5,5-dimethyl-2-[7-(2,3,6-trifluorobenzyl)imidazo[1,5-b]pyridazine-5-yl]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidine-6-one (21), 4-amino-2-[6-chloro-3-(2,3,6-trifluorobenzyl)imidazo[1,5-a]pyridine-1-yl]]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidine-6-one (22), 4-amino-2-[6-fluoro-3-(2,3,6-trifluorobenzyl)imidazo[1,5-a]pyridine-1-yl]]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidine-6-one (23), 4-amino-2-[6-fluoro-3-(2,3,6-trifluorobenzyl)6-fluoroimidazo[1,5-a]pyridine-1-yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidine-6-one (24), 4-amino-5,5-dimethyl-2-[3-(2,4,6-trifluorobenzyl)imidazo[1,5-a]pyridine-1-yl]]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidine-6-one (25), 4-amino-2-[3-(2-cyclopentylethyl)imidazo[1,5-a]pyridine-1-yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidine-6-one (26), 3-(4-amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine (27), and 2-{5-fluoro-1-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}-5-methyl-5-(trifluoromethyl)-4-[(3,3,3-trifluoropropyl)amino]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (28) to a patient in need thereof. 
     
     
         30 . The method of  claim 29 , wherein the digital ulcers are concomitant to fibrotic diseases that are systemic sclerosis or scleroderma. 
     
     
         31 . The method of  claim 29 , wherein the sGC stimulator or activator is selected from the group consisting of 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-5-(4-morpholinyl)-4,6-pyrimidinediamine (1), 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-5-(4-pyridinyl)-4-pyrimidine amine (2), methyl-4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-5-pyrimidinyl(methyl)carbamate (3), methyl-4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-5-pyrimidinylcarbamate (4), methyl-{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]pyrimidine-5-yl}carbamate (6), methyl-{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidine-5-yl}methylcarbamate (7), 3-(4-amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine (27), and 2-{5-fluoro-1-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}-5-methyl-5-(trifluoromethyl)-4-[(3,3,3-trifluoropropyl)amino]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (28). 
     
     
         32 . The method of  claim 28 , wherein a therapeutically effective amount of a sGC stimulator or activator in combination with a PDE5 inhibitor is administered. 
     
     
         33 . The method of  claim 32 , wherein the sGC stimulator or activator is selected from the group consisting of 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-5-(4-morpholinyl)-4,6-pyrimidinediamine (1), 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-5-(4-pyridinyl)-4-pyrimidine amine (2), methyl-4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-5-pyrimidinyl(methyl)carbamate (3), methyl-4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-5-pyrimidinylcarbamate (4), methyl-{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidine-5-yl}carbamate (6), methyl-{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]pyrimidine-5-yl}methylcarbamate (7), 3-(4-amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine (27), and 2-{5-fluoro-1-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}-5-methyl-5-(trifluoromethyl)-4-[(3,3,3-trifluoropropyl)amino]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (28) and the PDE5 inhibitor is selected form the group consisting of vardenafil, sildenafil, tadalafil, udenafil, dasantafil, avanafil, mirodenafil, lodenafil, UK 369.003, UK 371.800, SLx2101 and LAS34179.

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